Fibroblast growth factor receptor 3 associates with and tyrosine phosphorylates p90 RSK2, leading to RSK2 activation that mediates hematopoietic transformation

Sumin Kang, Shannon Elf, Shaozhong Dong, Taro Hitosugi, Katherine Lythgoe, Ailan Guo, Hong Ruan, Sagar Lonial, Han Na J. Khoury, Ifor R. Williams, Benjamin H. Lee, Johannes L. Roesel, Gerard Karsenty, André Hanauer, Jack Taunton, Titus J. Boggon, Ting Lei Gu, Jing Chen

Research output: Contribution to journalArticle

43 Scopus citations

Abstract

Dysregulation of the receptor tyrosine kinase fibroblast growth factor receptor 3 (FGFR3) plays a pathogenic role in a number of human hematopoietic malignancies and solid tumors. These include t(4;14) multiple myeloma associated with ectopic expression of FGFR3 and t(4;12)(pl6;pl3) acute myeloid leukemia associated with expression of a constitutively activated fusion tyrosine kinase, TEL-FGFR3. We recently reported that FGFR3 directly tyrosine phosphorylates RSK2 at Y529, which consequently regulates RSK2 activation. Here we identified Y707 as an additional tyrosine in RSK2 that is phosphorylated by FGFR3. Phosphorylation at Y707 contributes to RSK2 activation, through a putative disruption of the autoinhibitory αL-helix on the C terminus of RSK2, unlike Y529 phosphorylation, which facilitates ERK binding. Moreover, we found that FGFR3 interacts with RSK2 through residue W332 in the linker region of RSK2 and that this association is required for FGFR3-dependent phosphorylation of RSK2 at Y529 and Y707, as well as the subsequent RSK2 activation. Furthermore, in a murine bone marrow transplant assay, genetic deficiency in RSK2 resulted in a significantly delayed and attenuated myelopro-liferative syndrome induced by TEL-FGFR3 as compared with wild-type cells, suggesting a critical role of RSK2 in FGFR3-induced hematopoietic transformation. Our current and previous findings represent a paradigm for tyrosine phosphorylation-dependent regulation of serine-threonine kinases.

Original languageEnglish (US)
Pages (from-to)2105-2117
Number of pages13
JournalMolecular and cellular biology
Volume29
Issue number8
DOIs
StatePublished - Apr 2009

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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    Kang, S., Elf, S., Dong, S., Hitosugi, T., Lythgoe, K., Guo, A., Ruan, H., Lonial, S., Khoury, H. N. J., Williams, I. R., Lee, B. H., Roesel, J. L., Karsenty, G., Hanauer, A., Taunton, J., Boggon, T. J., Gu, T. L., & Chen, J. (2009). Fibroblast growth factor receptor 3 associates with and tyrosine phosphorylates p90 RSK2, leading to RSK2 activation that mediates hematopoietic transformation. Molecular and cellular biology, 29(8), 2105-2117. https://doi.org/10.1128/MCB.00998-08